Field of invention

The present invention relates to process for the preparation of 6-O-methylerythromycin A of formula (I) via selective methylation of hydroxy group at the 6 position of erythromycin A derivative.

Background of the invention

6-O-methylerythromycin A is a semi-synthetic macrolide antibiotic of formula (I), chemically know as Clarithromycin. It is a semi synthetic macrolide antibiotic which exhibits strong antibacterial activity towards a wide range of bacteria inclusive of gram positive bacteria, some gram negative bacteria, anaerobic bacteria, mycoplasma, chlamydia and helicobacter pylori, and because of its high stability in acidic environment of the stomach, it can be orally administered to treat respiratory organ diseases, and also to prevent recurrence of ulcer when used in combination with other medicine.

U.S. Pat. No. 4,331,803 discloses a method for methylating a hydroxy group at the 6-position of erythromycin A derivatives, with a methylating agent in the presence of a base in a polar solvent. This method is not selective as it gives compounds which are methylated at hydroxy groups other than the 6-position along with the 6-0-methyl form Therefore, it requires several purification to get the intended pure 6-0-methyl form which reduces the yield drastically.

U.S. Pat. No. 4,672,109 discloses selective methylation methylating agent in the presence of a base by the use of a polar aprotic solvent such as dimethyl sulphoxide (DMSO), N, N-dimethylformamide (DMF), hexamethylphosphoric triamide, a mixture consisting of two or more of these solvents, or a mixture consisting of one of these solvents and tetrahydrofuran. The most preferred example of the solvents in the prior art is the mixture of DMSO and tetrahydrofuran for affecting the desired methylation followed by quenching with aqueous dimethylamine solution and extraction with hexanes. A major drawback of this process is use of tetrahydrofuran as its combustive and explosive nature due to contamination of peroxide. Another major drawback of this process is recovery of tetrahydrofuran and combustive and explosive nature. Tetrahydrofuran is an expensive solvent and adds a important cost factor in the overall cost of production of clarithromycin. Therefore, nonattainment of the recovery of tetrahydrofuran makes the said process expensive and makes it unattractive on a commercial scale.

US 6900296 discloses selective methylation at the 6-position of erythromycin A derivatives with methylating agent in the presence of a base in a mixture of toluene and polar aprotic solvent. This process remains silent about % of unknown impurities associated with final product.

WO 2006064299 discloses selective methylation at the 6-position of erythromycin A derivatives with methylating agent in the presence of a base in a mixture of polar aprotic solvent such as N, N dimethyl sulphoxide (DMSO) and diethyl ether. A drawback of this process is use of diethyl ether as its combustive and explosive nature due to formation of peroxide.

WO 2006100691 discloses selective methylation at the 6-position of erythromycin A derivatives with methylating agent in the presence of a base in a mixture of polar aprotic solvent such as N, N dimethyl sulphoxide (DMSO) and cyclic or acyclic alkane having C6-C10 carbon atoms. This process remains silent about yield and recovery of solvents.

WO 2007029265 discloses selective methylation at the 6-position of erythromycin A derivatives with methylating agent in the presence of a base in a mixture of chlorinated hydrocarbon, polar aprotic solvent and a nonpolar solvent. This process also remains silent about recovery of solvents.

The purity of an API produced in a manufacturing process is critical for commercialization. The U.S. Food and Drug Administration ("FDA") requires that process impurities be maintained below set limits. For example, in its ICH Q7A guidance for API manufacturers, the FDA specifies the quality of raw materials that may be used, as well as acceptable process conditions, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction. See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version (Nov. 10, 2000).

The product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product. The FDA requires that an API is as free of impurities as possible, so that it is as safe as possible for clinical use. For example, the FDA recommends that the amounts of impurities be limited to less than 0.1 %. See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version (Nov. 10, 2000).

Therefore, there is a need to develop a high yield process which provides high yield and purity 6-O-methylerythromycin A according to ICH guidelines by devoiding drawbacks associated with prior art processes.

It has been serendipitously found that process according to present invention provides 6-O-methylerythromycin A having purity at least 98.5 % and individual unknown impurity less than 0.1% with high yield as well as it provides greater recovery of solvents which makes this process cost effective on commercial scale.

Object of the invention

A primary object of the present invention is to provide a process of the preparation of 6-O-methylerythromycin A which results in increased yield and purity.

Another object of the present invention is to provide a process of the preparation of 6-O-methylerythromycin A which is simple, easy to handle and cost effective on commercial scale.

Yet another object of the present invention is to provide a process for the preparation of 6-O-methylerythromycin A (I) having purity at least 98.5% and individual unknown impurity less than 0.1% comprising a step of methylating erythromycin A derivative with methylating agent in mixture of chlorobenzene and polar aprotic solvent in the presence of base.

A further object of the present invention is to provide a process for the preparation of 6-O-methylerythromycin A (I) comprising a step of methylating erythromycin A derivative with methylating agent in mixture of chlorobenzene and polar aprotic solvent in the presence of base.

Summary of the invention

According to one aspect of the invention, it provides a process for the preparation of 6-O-methylerythromycin A (I) comprising a step of methylating erythromycin A derivative with methylating agent in mixture of chlorobenzene and polar aprotic solvent in the presence of base.

Brief Description of figure

Fig. 1 depicts an HPLC chromatogram of 6-O-methyl erythromycin A.

Detailed description of the invention

The present invention provides a process for carrying out selective methylation at 6-position of erythromycin A derivatives in which the term "erythromycin A derivative" means erythromycin A having no substituent group or having conventional substituent groups in organic synthesis, in place of a hydrogen atom of the 2'' and 4" hydroxy groups and/or a methyl group of the 3''-dimethyl amino group which is prepared according to the conventional manner. Erythromycin A derivatives also include 2'', 4"-bis trimethyl silyl or as 2''-carbobenzyloxy or as 3''-dicarbobenzyloxy erythromycin A derivatives. Further the term erythromycin A derivatives also include "erythromycin A 9 oximes" having at the 9-position the general formula,

wherein R is a hydrogen atom or a substituent group such as lower alkyl group, which is substituted, or unsubstituted, an aryl substituted methyl group, a substituted oxyalkyl group or a thioalkyl group. It may also includes any derivative of erythromycin A in which any group of erythromycin A may be substituted with another group.

The term “erythromycin A derivative” as used herein refers to erythromycin A derivative of any purity and may be solid, semisolid, or in form of syrup or it may exists in any crystalline forms. Erythromycin A derivative used in the process of present invention can be prepared by any of methods disclosed in prior art.

Accordingly, the present invention relates to a process, which comprises dissolving erythromycin A derivative in a mixture of chlorobenzene and polar aprotic solvent and reacting it with a methylating agent in the presence of a base. The ratio of chlorobenzene and polar aprotic solvent varies from 1:1 to 1:5, preferably 1:1.

The meaning of term “polar aprotic solvent” includes but not limited to dimethyl sulphoxide, N, N-dimethylformamide, hexamethyl phosphoric triamide and the like or mixture thereof.

The meaning of term “methylating agents” includes but not limited to methyl halides such as methyl iodide, methyl bromide and the like; dimethyl sulphate, methyl p-toluene sulphonate, methyl methane sulphonate and the like or mixture thereof. The preferred one is methyl iodide.

The meaning of term “base” includes but not limited to potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride and the like or mixture thereof. The preferred one is potassium hydroxide.

The methylation reaction of present invention may be carried out at a temperature up to 100 0C., preferably at 5-25 0C., more preferably at 5-15 0C. However, carrying out the methylation reaction at higher temperature leads to the formation of undesired products and therefore, requires extra purification to get the pure 6-0-methyl form which reduces the yield. The methylation reaction is efficiently accomplished in 1-2 hours. However, the length of time required will vary depending upon such factors as temperature of reaction, concentration and presence or absence of efficient stirring.

After the reaction is over the reaction mixture is quenched in aqueous dimethylamine solution and more water is added. Chlorobenzene layer is separated and subjected to vacuum distillation to recover pure chlorobenzene as a recovered solvent and desired methylated compound.

After isolating 6-O-methyl Erythromycin A of formula (I), it may be further purified by recrystallization from suitable known solvent. If required carry out repeated crystallization from suitable known solvent to get the desired purity of the compound.

In the examples, purity of obtained compounds was analyzed by HPLC with column C-18, 3.5µ Endcapped, at 205 nm.

The examples given below illustrate the process of the present invention but do not intend to limit the scope of the present invention.

Example 1: Preparation of crude 6-O-methyl Erythromycin A

Erythromycin oxime (100 gm) was added in methylene dichloride (600 ml) at room temperature. 50 ml of methylene dichloride was distilled out azeotropically to remove moisture from reaction. The reaction mass was chilled to 0 to 5 °C. 2-Methoxy propene (30 gm) and pyridine Hydro bromide (25gm) was added at 0 to 5 °C to reaction mass. The temperature of reaction mass was raised upto 15 to 20 °C and stirred for 180 minutes at 15 to 20 °C. After completion of reaction, the reaction mass cooled at temperature 10 to 15 °C. Hexamethyldisilazane (30 gm) was added in reaction mass and stirred for 90 min at 15 to 20 °C. After completion of reaction, sodium bicarbonate solution (15 gm sodium bicarbonate dissolved in 200 ml DM Water) was added to reaction mass and cooled 5 to 10 °C. The reaction mass was stirred and allowed the layer to settle. The organic layer was extracted and washed with DM water and 10% Sodium chloride solution. The organic layer of methylene dichloride were distilled out completely from the reaction mass by applying vacuum till no traces of methylene dichloride. Chloro benzene (500 ml) was added in to the reaction mass. Chlorobenzene was completely distilled out under vacuum from reaction mass. The reaction mass was cooled to 25 to 30 °C. Chlorobenzene (2000 ml) was again added in to the reaction mass and stirred. Dimethyl sulfoxide (2000 ml) was added in the reaction mass & stirred it. The reaction mass was cooled to 5 to 10 °C. Methyl Iodide (25 gm) and KOH Powder (10 gm) was added in to reaction mass at 5 to 10 °C. The reaction mass was stirred vigorously for 40 to 55 minute at 5 to 10 °C. 40% Dimethyl Amine solution (40 gm) was added in to the reaction mass. After completion of reaction, the reaction mass was stirred followed by adding of DM water (1000 ml). Layers were allowed to settle. The organic layer of chloro benzene was extracted and washed with DM water at 40 to 45 °C. Chloro benzene was distilled out completely and recovered from the reaction mass under vacuum (recovery of chlorobenzene  1800 ml, 90 % v/v). DM water was added in to the reaction mass two times and distilled out completely by applying vacuum. Ethyl Alcohol (325 ml) was added in to the reaction mass & stirred it at 30 to 35 °C. DM water (325 ml) & formic acid (20.89 gm) was added in to the reaction mass followed by addition of sodium metabisulphite (254 gm) at 30 to 35 °C. The reaction mass was heated at 55 to 65 °C and stirred. After completion of reaction, the reaction mass was cooled between 35 to 40 °C. DM water was added in to the reaction mass. NaOH solution (100 gm NaOH dissolved in 600 ml DM water) was added in to the reaction mass and pH adjusted to 10 to 12 at 35 to 40 ° C. The reaction mass was stirred at 35 to 40 °C. Again DM water (400 ml) was added in to the reaction mass and pH was checked. A product was filtered and washed with hot DM water. The product was dried at 80 °C-85 °C to get crude 6-O-methyl Erythromycin A.

Example 2: Preparation of pure 6-O-methyl Erythromycin A

Crude 6-O-methyl Erythromycin A (100 gm) was added Ethanol (300 ml) at room temperature and stirred. The reaction mixture was heated at temperature between 75 to 80 °C. The reaction mixture was refluxed for 90 minutes at temperature between 75 to 80 °C. The reaction mixture was cooled at temperature between 25 to 35 °C and stirred. The product was filtered, washed with Ethyl Alcohol and suck dried to get wet cake. Wet cake was added into ethanol (300 ml) at room temperature and stirred. The reaction mixture was heated at temp between 75 to 80 °C and refluxed for 90 minutes at temp between 75 to 80 °C. The reaction mixture was cooled at temp 25 to 35 °C and stirred. The product was filtered, washed wet cake with Ethyl Alcohol and suck dried to get wet cake. Wet cake was added to ethyl alcohol (14.82 L) at room temperature and stirred. The reaction mixture was heated at 75 to 80 °C followed by addition of activated charcoal (2 gm). The reaction mixture was stirred & refluxed. A reaction mixture was passed through hyflo bed at temp 75 to 80 °C and washed hyflo bed with hot ethyl alcohol. A filtrate was heated at temp 75 to 85 °C. Ethyl alcohol was distilled out from the reaction mixture till residual volume. Then a reaction mass was stirred at temperature 70 to 80 °C and cooled at temperature 28 to 35 °C. The reaction mass was stirred at temp 28 to 35 °C, filtered and suck dried to obtain wet 6-O-methyl Erythromycin A. Wet 6-O-methyl Erythromycin A was dried at temp 80 to 105 °C under humid air circulation to obtain 6-O-methyl Erythromycin A.
Yield  60-70 %
HPLC purity  98.5 -100 %